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Park BY, Saint-Jeannet JP. Induction and Segregation of the Vertebrate Cranial Placodes. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Induction and Segregation of the Vertebrate Cranial Placodes.

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Molecular Identity of Cranial Placodes

All vertebrate cranial placodes originate from a common territory known as the pre-placodal or pan-placodal ectoderm, adjacent to the anterior neural plate (Figure 1). Studies in the chick embryo using focal dye labeling have shown that within the pre-placodal region, precursors for different placodes are initially intermingled, still some separation of individual populations along the anterior posterior axis is already apparent at the end of gastrulation (Streit, 2002; Bhattacharyya et al., 2004). Precursors for anterior placodes (adenohypophysis, olfactory, lens) are located in the rostral most pre-placodal region, while precursors for posterior placodes (trigeminal, epibranchial, otic, lateral line) are restricted more caudally (Figure 1; D’Amico-Martel and Noden, 1983; Kozlowski, et al., 1997; Streit, 2002; Bhattacharyya, et al., 2004). This subdivision can be visualized by the regional expression of transcription factors, shortly after the induction of the pre-placodal domain. As development proceeds, the pre-placodal region becomes molecularly divided into smaller sub-domains such that by the time placodes can be identified morphologically, each appears to express a unique combination of transcription factors - a transcriptional code that may underlie their identity. This is illustrated in Figure 9, for the expression of a several transcription factors during cranial placode development in Xenopus. These genes include the transcription factors Six1 (Pandur and Moody, 2000), initially broadly expressed in the entire pre-placodal region; Pax8 (Heller and Brandli, 1999), restricted to a posterior sub-domain of the pre-placodal region, corresponding to precursors of the otic and lateral line placodes; Dmrt4 (Huang et al., 2005), confined anteriorly to the prospective regions of the adenohypophyseal and olfactory lens placodes; Foxi1c (Pohl et al., 2002) expressed on the anlagen of the epibranchial and lateral line placodes; Pax6 (Hirsch and Harris, 1997), expressed in the neural plate and in precursors of the olfactory and lens placodes; and Ngnr1 (Perron et al., 1999), expressed in the trigeminal /profundal placode (Figure 9A). Later in development and as the placodes segregate from one another, the expression of these genes may persist in various combinations in the placode derivatives, concomitant to the differential activation of novel genes, such as Tbx2 (Takabatake et al., 2000) expressed in the otic and trigeminal/profundal placodes, and Lens1 (Kenyon et al., 1999) restricted to the lens placode (Figure 9B–C).

Figure 9. Whole-mount in situ hybridization of several transcription factors differentially expressed in the Xenopus laevis cranial placodes.

Figure 9

Whole-mount in situ hybridization of several transcription factors differentially expressed in the Xenopus laevis cranial placodes. (A) Expression of genes in the pre-placodal domain at the early neurula stage (stage 15). Left panels are anterior views, (more...)

The gene regulatory network underlying cranial placode development has been the focus of intense investigation in the last decade, and it is just beginning to be unraveled (reviewed in Baker and Bronner-Fraser, 2001; Streit, 2004; Battacharrya and Bronner-Fraser, 2004; Schlosser and Ahrens, 2004; Brugmann and Moody, 2005; Schlosser, 2006; Bailey and Streit, 2006; McCabe and Bronner-Fraser, 2009). In the following tables we summarize the expression of transcription factors during the development of the seven cranial placodes and their derivatives. These tables will compare data from multiple vertebrate species, including fish, frog, chick and mouse, as follow: adenohypophyseal placode (Table 1), olfactory placode (Table 2), lens placode (Table 3), trigeminal /profundal placode (Table 4), otic placode (Table 5), epibranchial placode (Table 6) and lateral line placode (Table 7). For each gene, the listed references report the expression pattern, and when available, the function of the gene in the corresponding placode. These tables are not intended to be an exhaustive compilation of all the transcription factors within the cranial placodes and their derivatives but more a summary of the current knowledge as a way to gain insight into the molecular identity of these placodes.

TABLE 1. Expression of transcription factors during adenohypophyseal placode development.

TABLE 1

Expression of transcription factors during adenohypophyseal placode development.

TABLE 2. Expression of transcription factors during olfactory placode development.

TABLE 2

Expression of transcription factors during olfactory placode development.

TABLE 3. Expression of transcription factors during lens placode development.

TABLE 3

Expression of transcription factors during lens placode development.

TABLE 4. Expression of transcription factors during trigeminal /profundal placode development.

TABLE 4

Expression of transcription factors during trigeminal /profundal placode development.

TABLE 5. Expression of transcription factors during otic placode development.

TABLE 5

Expression of transcription factors during otic placode development.

TABLE 6. Expression of transcription factors during epibranchial placode development.

TABLE 6

Expression of transcription factors during epibranchial placode development.

TABLE 7. Expression of transcription factors during lateral line placode development.

TABLE 7

Expression of transcription factors during lateral line placode development.

A few years ago, Meulemans and Bronner-Fraser (2004), presented a comprehensive analysis of the regulatory network of genes expressed at the neural plate border, which includes neural crest and placodes. In this model they proposed that in response to signaling events a number of transcriptions factors are sequentially induced at the neural plate border in a two-step process. First, a group of genes is activated, referred as “neural plate border specifiers,” which includes members of the Zic, Pax, Dlx and Msx families of transcriptional regulators. These factors, which are broadly expressed at the neural plate border, are in turn responsible for the activation of a subset of genes with more restricted expression domains, known as “neural crest specifiers” (Meulemans and Bronner-Fraser, 2004) or “pre-placodal specifiers” (Litsiou et al., 2005). The function of these neural crest and pre-placodal specifiers is to control the expression of genes regulating the behavior and differentiation patterns of these two cell lineages. Significant advances have been made over recent years into the regulation of placode formation, which has helped in drafting a constantly evolving gene regulatory network underlying vertebrate placode development. Among the key regulators of placode development are the Six, Eya and Pax gene families, which are expressed by all vertebrate sensory placodes and constitute an important branch of this regulatory network. This specific topic has been reviewed in a number of excellent recent articles (Streit, 2004; 2007; Battacharrya and Bronner-Fraser, 2004; Schlosser and Ahrens, 2004; Brugmann and Moody, 2005; Schlosser, 2006; Schlosser, 2007; Bailey and Streit, 2006; McCabe and Bronner-Fraser, 2009), and will be only briefly summarized here.

Six and Eya gene families

In vertebrates, the Six and Eya gene families have six (Six1–6) and four (Eya1–4) members, respectively. Six genes encode transcription factors with direct DNA-binding capacity, while Eya genes encode nuclear proteins with tyrosine phosphatase activity. Eya proteins affect transcription indirectly by interaction with other proteins including Six transcription factors (reviewed in Kawakami et al., 2000; Rebay et al., 2005; Kumar, 2009). Six and Eya genes were first identified in Drosophila as sine oculis (so) and eyes absent (eya). Mutations in either gene show severe eye phenotypes in flies, and Six-Eya combined overexpression can induce ectopic eyes (Bonini et al., 1993; Pignoni et al., 1997).

These genes are not only expressed in the pre-placodal ectoderm, but also later in most cranial placodes and their derivatives (see Tables 17 for references). Mutations in Eya1 and Six1 genes in humans, mice, and zebrafish show a very similar spectrum of defects in various placode derivatives suggesting that they are important regulators of placodal development. Mice heterozygous for Eya1 have hearing loss due to defects of the middle ear (Xu et al., 1999), a phenotype similar to the one observed in patients affected by Branchio-Oto-Renal syndrome caused by a mutation in the EYA1 gene (Abdelhak et al., 1997). Homozygous Eya1 mutant mice display much more severe inner ear defects. Otic placode formation is initiated normally but development arrests at the vesicle stage and the vestibulochochlear ganglia do not form. In addition, the epibranchial placode-derived ganglia are missing (Xu et al., 1999). Mutations in the human EYA1 gene also lead to congenital eye defects (Azuma et al., 2000). Mice lacking Six1 function display inner ear abnormalities similar to the defects observed in Eya1 homozygous mutant mice: the otic vesicle fails to expand leading to an absence of cochlear duct and semicircular canals (Laclef et al., 2003; Li et al., 2003; Zheng et al., 2003). Like Eya1 mutant mice, Six1 homozygous mutant mice lack both the vestibulochochlear and petrosal ganglia. However, a complete loss of placodal derivatives in any of these mutants has not been observed as one might expect from genes involved in establishing the pre-placodal domain. Since several members of the Six and Eya families are co-expressed in this region the lack of an early phenotype may be due to functional redundancy. Consistent with this possibility, Six1/Six4 compound mice have trigeminal ganglion defects, a phenotype not seen in the single mutants (Grifone et al., 2005; Konishi et al., 2006).

In zebrafish dog-eared mutants carry a mutation in the eya1 gene. In this organism, Eya1 function appears to be primarily required for survival of sensory hair cells in the developing ear and lateral line neuromasts (Whitefield et al., 1996; Kozlowski et al., 2005). In Xenopus overexpression of Six1 leads to an expansion of the pre-placodal region at the expense of neural plate, neural crest, and epidermis, in contrast Six1 morpholino-mediated knockdown results in the loss of pre-placodal markers at early stage, including Eya1 (Brugmann et al., 2004; Brugmann and Moody, 2005). A later phenotype of Six1-depleted Xenopus embryos has not been reported.

Altogether these observations point to an essential role for Six1 and Eya1 in early placode development. The precise molecular function of these genes in the pre-placodal region is still unclear. They could confer placodal competence to the ectoderm or bias the anterior neural plate border toward a placode fate as recently suggested (Streit, 2004, Bailey and Streit, 2006). It is remarkable that this network of genes has been conserved during evolution to specify sensory organs in Drosophila and in vertebrates (Schlosser, 2007).

Pax gene family

Pax genes encode a DNA-binding domain termed the paired domain and in addition some also encode a second binding domain, a paired type homeobox. Pax genes regulate a broad array of developmental processes including proliferation, differentiation, cell adhesion, and signaling. These genes are divided into four groups based on sequence similarity: Pax1/Pax9 group, Pax2/Pax5/Pax8 group, Pax3/Pax7 group and Pax4/Pax6 group (reviewed in Dahl et al., 1997; Chi and Epstein, 2002). Among the different Pax genes only Pax2/5/8, Pax3/7, and Pax6 have been implicated in placode development. All placodes express one or more Pax gene at a relatively early stage in their development. Pax8 is an early marker of the otic placode; Pax6 is a well-known and essential regulator of the lens placode and olfactory placodes; Pax3 is the earliest known marker for the ophthalmic branch of the trigeminal ganglion, while Pax2 is expressed early in both the otic and epibranchial placodes.

The three vertebrate genes of the Pax2/5/8 group are expressed in a broad range of tissues including the kidney, thyroid, thymus and central nervous system (reviewed in Dahl et al., 1997; Chi and Epstein, 2002). Early on in embryogenesis Pax2 and Pax8 are also expressed in the posterior placodal area at neural plate stages, with maintained expression in the developing otic and epibranchial placodes (see Tables 17 for references). Work in the chick suggests that Pax2 controls epibranchial neuron identity (Baker and Bronner-Fraser, 2000). In zebrafish, Pax2 and Pax8 function synergistically to specify the otic placode (Hans et al., 2004), but act redundantly to maintain the otic placode (Mackereth et al., 2005). By contrast mice lacking Pax8 function have no obvious inner ear phenotype (Mansouri et al., 1998), while Pax2 mutant mouse embryos display agenesis of the cochlear duct and associated ganglion (Torres et al., 1996; Burton et al., 2004).

Pax3 and Pax7 are two important regulators of myogenesis, however, they are also expressed in the dorsal neural tube and during neural crest development (reviewed in Dahl et al., 1997; Chi and Epstein, 2002). Pax3 is also detected in the profundal placode where it is implicated in establishing neuron identity (Baker and Bronner-Fraser, 2000; Baker et al., 2002). In the Pax3 mouse mutant, Splotch (Pax3Splotch), several cranial ganglia are hypoplastic including the trigeminal ganglion (Epstein et al., 1991; Tremblay et al., 1995). This phenotype is also associated with severe defects in the formation of the cochlear duct and vestibulocochlear ganglion (Buckiova and Syka, 2004). Placode defects have not been analyzed in Pax3-depleted Xenopus embryos (Monsoro-Burq et al., 2005).

Pax6 is implicated in the formation of the most anterior placodes (reviewed in Gehring and Ikeo, 1999; Bhattacharyya and Bronner-Fraser, 2004). Pax6 is expressed in the central nervous system and in the ectoderm that will give rise to the adenohypophyseal, olfactory and lens placodes (see Tables 17 for references). Pax6 is best known for regulating lens differentiation by binding directly to the enhancers of crystallin genes to regulate their expression (review in Chow and Lang, 2001; Cvekl et al., 2004). Pax6 overexpression leads to ectopic formation of eyes and lens placodes (Altmann et al., 1997; Chow et al., 1999), an activity very well conserved during evolution (Gehring and Ikeo, 1999). On the other hand Pax6 mutant mouse embryos, Small eyes (Pax6Sey), show reduced eyes with missing lens and olfactory placodes (Hogan et al., 1986). In the Pax6 mutants the adenohypophyseal placode is also defective (Bentley et al., 1999).

Pax, Six and Eya genes are part of the same regulatory network during placode development. However, Pax genes are expressed in a more restricted manner, suggesting that they may have a more specific role in promoting placode identity within a pre-placodal region established by Six and Eya (Baker and Bronner-Fraser, 2001; Streit, 2002,2004; Schlosser and Ahrens, 2004; Schlosser, 2006). The mechanism by which Pax genes regulate placode identity is not understood, but is likely to involve others families of transcription factors (see Tables 17). In addition, and because their expression is maintained in derivatives of several cranial placodes Pax genes are also likely to regulate other aspects of placode development, including morphogenesis, patterning and differentiation.

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Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53173

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